EP0210204B1 - Proteinhydrolysate, verfahren zu ihrer herstellung und arzneimittel, die diese hydrolysate enthalten - Google Patents

Proteinhydrolysate, verfahren zu ihrer herstellung und arzneimittel, die diese hydrolysate enthalten Download PDF

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Publication number
EP0210204B1
EP0210204B1 EP86900765A EP86900765A EP0210204B1 EP 0210204 B1 EP0210204 B1 EP 0210204B1 EP 86900765 A EP86900765 A EP 86900765A EP 86900765 A EP86900765 A EP 86900765A EP 0210204 B1 EP0210204 B1 EP 0210204B1
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Prior art keywords
approximately
product
protease
process according
temperature
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Expired
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EP86900765A
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German (de)
English (en)
French (fr)
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EP0210204A1 (de
Inventor
Kailash Kumar Dr. Prof. Gauri
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Priority claimed from DE19853501560 external-priority patent/DE3501560A1/de
Priority claimed from DE19853518828 external-priority patent/DE3518828A1/de
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Priority to AT86900765T priority Critical patent/ATE39046T1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to a protein hydrolyzate obtained from whey protein, lactalbumin, a-lactalbumin, lactoferrin, ⁇ -lactoglobulin, lysozyme or serum albumin, a process for the preparation of this hydrolyzate and its use for pharmaceutical purposes.
  • milk proteins are made up of caseins and whey proteins.
  • proteose peptones account for about 5% of the total nitrogen content in cow's milk.
  • the proportion of caseins in the total protein content of cow's milk is about 80%, that of whey proteins about 20%.
  • the caseins are among the best researched proteins. Contrary to the original assumptions, they are by no means uniform bodies. So far, several groups have been distinguished. However, it is typical of all caseins that they contain bound phosphorus. They are much more complex and have a much greater molecular weight than the so-called whey proteins. Whey proteins have hitherto been known to consist of ⁇ -lactoglobulin, ⁇ -lactalbumin, serum albumin and immunoglobulins.
  • the invention has for its object to provide other pharmaceutically useful components from certain other proteins.
  • the protein hydrolyzate according to the invention is obtainable by mixing about 1 to 10% by weight of whey protein, lactalbumin, lactoferrin, ⁇ -lactalbumin, ⁇ -lactoglobulin, lysozyme or serum albumin and water.
  • the treatment at 35 to 38 ° C. preferably lasts for about 1 to 4 hours, advantageously about 2 hours and the elevated temperature of about 60 ° C. is advantageously maintained for about 1 to 4, preferably about 2 to 3 hours.
  • Absolute ethanol, chloroform or isopropanol is preferably used as the polar solvent and a chloroform / methanol mixture (1/1 to 3/1 vol./vol.) Or an ethanol-water mixture with 20 to 80% water is recommended as the polar solvent mixture use.
  • the protease (s) used are preferably papain, pancreatin, chymotrypsin, trypsin and, if appropriate, a protease obtained from fungi and / or bacteria, the fungal protease being selected from the proteases from Tritirachium species, in particular Tritirachium alba, proteases from Aspergillus species, in particular Aspergillus saitoi, Aspergillus sojae, Aspergillus oryzae and / or from Rhizopus species, in particular Newlase, and where the bacterial protease is selected from proteases from Streptomyces species, in particular Streptomyces caespitosus, Streptomyces griseus (Pronase E), from Bacillus subtilis species, in particular subtilopeptidase A (Carlsberg subtilisin), and from Bacillus polymyxa.
  • Tritirachium species in particular Tritirachium alba
  • an a-amylase from a Subtilis species.
  • the optimum activity of such an amylase is usually at a pH of 5.7 to 7.2 and the temperature can go up to 75 ° C.
  • the enzymes are advantageously used in an amount of about 0.01 to 2% by weight, based on the suspension.
  • Papain or a mixture of approximately equal parts by weight of pancreatin and papain is preferably used as the protease.
  • Another advantageous protease mixture is a mixture of approximately equal proportions of papain, pancreatin and a bacterial or fungal protease, for example the bacterial protease Pronase E from Streptomyces griseus and as a fungal protease the product “Newlase” from an Aspergillus species.
  • the heat-resistant enzymes are preferably added in the second heating phase, that is to say after the first heating to 35 to 38 ° C.
  • the above-mentioned product (AP) can be further purified and separated by suspending this product in about 10 to 20 times the amount by weight of a 40 to 80% aqueous ethanol, with about the same volume of an aliphatic or cycloaliphatic hydrocarbon with about 4 to 8 C atoms repeatedly extracted, the solvent removed from the individual phases (the aqueous alcoholic and the hydrocarbon extract), the product (A 2 ) being obtained as the residue of the aqueous alcoholic phase and the product (P) as the residue of the hydrocarbon extract.
  • the product (A 2 ) is advantageously extracted with about 5 to 20 times the amount by weight of diethyl ether, the undissolved portion is stirred vigorously with about 20 to 40 times the amount of chloroform, then filtered, the filtrate is evaporated to dryness and thus the product (F) isolated.
  • the chloroform-insoluble part is the product (N).
  • the ether extract obtained in the treatment of product (A 2 ) can advantageously be concentrated and the residue obtained in this way can be combined with the above-mentioned product (P).
  • the latter can advantageously be dissolved in absolute ethanol for further purification, H 2 0 is added to a constant turbidity and then extracted with an aliphatic or cycloaliphatic hydrocarbon having about 4 to 8 carbon atoms.
  • purified product (P) is obtained which is solid at room temperature but becomes liquid above 30 ° C.
  • further product (A 2 ) can be obtained from the aqueous-ethanolic phase by concentration, which, as already described above, can be processed further and, in the separation described, predominantly yields product (F).
  • the products (F) and (N) described above can contain chloroform residues, these can be removed by dissolving the products (F) and! N) in a little ethanol and removing the ethanol in vacuo.
  • the aliphatic and cycloaliphatic hydrogens with 4 to 8 carbon atoms mentioned above are preferably n-hexane, cyclohexane, heptane, octane or petroleum ether with a boiling range of about 40 to 70 ° C.
  • the protein hydrolyzates obtainable according to the invention have valuable pharmacological properties. They work e.g. analgesic, anti-inflammatory, anti-mutagen and have an anti-glaucoma effect. You can e.g. for the treatment of painful inflammations of all kinds, neurodermatitis, arthritis, rheumatism but also glaucoma. Products (AB) and (A) according to the invention have predominantly analgesic, anti-mutagenic and anti-inflammatory effects.
  • the product F according to the invention is particularly characterized by its anti-inflammatory and anti-glaucoma effect.
  • the product N according to the invention is mainly analgesic and antimutagenic.
  • the product P according to the invention is advantageously suitable as an ointment base.
  • the product (N) according to the invention obtained from lactoferrin shows a particularly pronounced antimutagenic effect.
  • the invention also relates to pharmaceutical compositions which contain at least one of the protein hydrolyzates according to the invention, optionally together with a carrier and / or excipient suitable for pharmaceutical purposes.
  • compositions can be used particularly in the indications given above, e.g. can be used orally, parenterally or topically.
  • the dosage depends primarily on the specific form of processing and the purpose of the therapy or prophylaxis.
  • the single dose When administered orally, the single dose is generally between 0.5 and 50 mg (for an adult human with a body weight of about 70-75 kg) and about 3-10 doses per day (24 hours) are administered.
  • the lower dose range e.g. at 1.5-3 mg of active ingredient per single dose. With this dosage, the itching disappears quickly and then the skin normalizes.
  • the daily dose can be up to 500 mg (in an adult).
  • intravenous administration usually 70-140 mg per person (of about 75 kg body weight) are administered per day. As a rule, this dose is administered once a day.
  • a preparation for oral use can be used as a solution, e.g. be formulated in water or alcohol or as a tablet, and the usual physiologically acceptable fillers, binders, disintegrants and lubricants can be used for tablet production.
  • suitable fillers are e.g. Milk sugar, cane sugar, starch or cellulose and their derivatives.
  • Useful binders are e.g. Starch, gelatin, sugar, cellulose ether, polymers, e.g. Polyvinyl pyrrolidone. Starch and starch ether can also be used as disintegrants.
  • Suitable lubricants and mold release agents are e.g.
  • Talc stearates or silicones, and highly disperse silicon dioxide or talc can be used as a flow regulator.
  • the tablets can also be formulated as coated tablets or as film-coated tablets.
  • the preparation can also be administered in a conventional soft gelatin or hard gelatin capsule.
  • aqueous solutions can be prepared for injection purposes.
  • the active ingredient can also be kept available as a lyophilisate, which is dissolved in a suitable aqueous diluent before use.
  • a preparation for topical use can be in the form of an aqueous solution, lotion, jelly, oily solution, suspension, fatty or emulsion ointment.
  • a preparation in the form of an aqueous solution is obtained, for example, by dissolving the active compounds according to the invention in an aqueous buffer solution of pH 4 to 7.5 and, if desired, a further active compound and / or a polymeric adhesive, e.g. Polyvinylpyrrolidone, and / or a preservative.
  • the concentration of the active ingredient is about 1 to 10% by weight.
  • An oily form of application for topical administration is obtained, for example, by suspending the active compounds according to the invention in an oil, optionally with the addition of swelling agents, such as aluminum stearate, and / or surface-active agents (surfactants) whose HLB value (hydrophilic-lipophilic balance) is below 10 lies how fatty acid monoesters of polyhydric alcohols, e.g. B. glycerol monostearate, sorbitan monolaurate, sorbitan monostearate or sorbitan monooleate.
  • swelling agents such as aluminum stearate, and / or surface-active agents (surfactants) whose HLB value (hydrophilic-lipophilic balance) is below 10 lies how fatty acid monoesters of polyhydric alcohols, e.g. B. glycerol monostearate, sorbitan monolaurate, sorbitan monostearate or sorbitan monooleate.
  • a fatty ointment is obtained e.g. by suspending the active compounds according to the invention in a spreadable fat base, optionally with the addition of a surfactant with an HLB value below 10.
  • An advantageous ointment base is the product (P) according to the invention.
  • a drop of a 5% solution of the product according to the invention (F) in 20% aqueous ethanol was administered orally three times a day to 12 patients suffering from neurodermatitis and therefore experiencing severe itching all over the body.
  • a second group of 12 patients served as a control group (only aqueous ethanol applied).
  • the itchiness disappeared in about 30 minutes after the application.
  • the skin inflammation had decreased significantly.
  • pancreatin and papain predominantly lead to anti-inflammatory peptides which have a protective effect against pentoxyfylline damage
  • pancreatin and / or papain and proteases from fungus or bacteria also gives peptides with an analgesic effect.
  • proteases that work at higher temperatures for example those from fungi and bacteria, lead to a high proportion of analgesic peptides.
  • a denatured milk protein fraction from whey (commercially available as lactalbumin, for example as lactalbumin sigma) are suspended in 95 ml of water, while stirring, 0.4 g of a mixture of approximately equal parts by weight of pancreatin, papain and a bacterial or Add fungal protease and warm to 35 to 37 ° C. At this temperature, the mixture is stirred for several hours until the reaction mixture is approximately clear. The mixture is then heated to 60 ° C, slowly increased to 80 ° C after about 1 hour, left at this temperature for a short time, cooled and concentrated in vacuo.
  • lactalbumin 5 g of lactalbumin are suspended in 130 ml of water, 50 mg of papain and 50 ml of pancreatin and 50 mg of a lipase are added, heated to 35 to 37 ° C., stirred at this temperature for about 2 hours, 50 mg of a commercially available fungal protease are added, e.g. Newlase and slowly increases the temperature (within about 2-3 hours) to 60 ° C. Then the temperature is briefly increased to 80 ° C., allowed to cool, the cloudy solution is concentrated in vacuo, the residue is taken up in ethanol, filtered and concentrated in vacuo. About 0.2 g of product (AP) is obtained.
  • AP product
  • Example 2 Analogously to Example 1, 5 g of lactalbumin are suspended in 130 ml of water. 50 mg of two proteolytic enzymes, e.g. Add papain and pancreatin, warm to 38 ° C and stir at this temperature for about 2 hours. The temperature is then raised to 80 ° C. and worked up according to Example 1. About 1.8 g of product are obtained.
  • two proteolytic enzymes e.g. Add papain and pancreatin
  • Example 2 Analogously to Example 1, 5 g of lactalbumin are suspended in 130 ml of water. 50 mg of papain are added, the mixture is warmed to 35 to 37 ° C., the mixture is stirred for one hour at this temperature, 50 mg of papain are added again, the mixture is stirred for about 2 hours, briefly heated to 80 ° C. and then concentrated Cool the mixture to dryness in vacuo. Then treat with Ethanoi / Wassser, As described in Example 1, about 1.7 g of product are obtained.
  • lactoblobulin or 5 g lactoferrin are hydrolyzed and worked up after adding 200 ml water with a mixture of 50 mg pancreatin, papain and fungal protease as described in Example 1. After precipitation with 70:30 ethanol: water, 5.6 g of a peptide mixture are obtained.
  • a lyophilized powder from tritirachium species in particular from tritirachium alba, with a protein content of approximately 90% and an activity of approximately 10 to 20 U / mg protein is used as the enzyme mixture.
  • proteases from Aspergillus species in particular Aspergillus saitoi with an activity of approximately 0.3 U / mg dry matter or Aspergillus sojae with the same activity or Aspergillus oryzae are used.
  • protease from Rhizopus species is used, with an activity of approximately 0.5 U / mg mass.
  • the enzyme is also called "Newlase".
  • the lactoglobulin peptide hydrolyzate achieves i.p. versus 300 mg / kg. Pentoxyphyllin a protective effect.
  • Example 6 1 g of ⁇ -lactoglobulin is hydrolyzed with pancreatin, papain and a bacterial protease (from yeast) in an amount of 10 mg each and worked up as described above.
  • the enzyme mixture is produced by decapulation with 50% ethoxylated fatty alcohol. It is an endopeptidase with an activity of approximately 440 Delft units / mg dry matter.
  • the density of the protein is 750 to 900 g / 1.
  • the optimum activity is at pH 7 to 11 and a temperature of around 60 ° C.
  • Streptomyces species in particular Streptomyces caespitosus with an activity of 0.7 to 1 U / mg dry matter, with Subtilis species with an activity of 7-15 U / mg protein, in particular the enzyme subtilopeptidase A ( Carlsberg, Subilisin), with Streptomyces griseus (Pronase E) with an activity of 4 U / mg dry matter, or Streptomyces griseus with an activity of 15 to 20 U / mg dry matter, or with Bacillus Polymyxa with an activity of about 0, 4 U / mg dry matter.
  • Streptomyces species in particular Streptomyces caespitosus with an activity of 0.7 to 1 U / mg dry matter
  • Subtilis species with an activity of 7-15 U / mg protein
  • subtilopeptidase A Carlsberg, Subilisin
  • Streptomyces griseus Pronase E
  • Streptomyces griseus with an activity of 15 to 20 U /
  • a-lactalbumin 100 g are hydrolyzed according to Example 6.
  • absolute ethanol is used instead of the ethanol / water mixture.
  • the yield is approximately 2.5 g.
  • the peptide mixture shows a local analgesic effect at concentrations between 0.3 and 3%.
  • the product according to the invention was tested pharmacologically in the mouse experiment in the following manner.
  • the product according to the invention is administered intraperitoneally or intravenously about 30 minutes beforehand in a dose of about 300 to 600 mg / kg, a 60 to 100% protective effect against pentoxyphylline-induced mortality is achieved.
  • the local analgesic effect was also tested on the human eye.
  • the antimutagenic effect was tested on the Hamster-Sister Chromatide Exchange Test.
  • the chloroform-soluble filter residue is taken up in 250 ml of ethanol and concentrated in vacuo.
  • the product (N) is thus obtained; Yield: 13 g.
  • a further 4 g of product are obtained by dissolving in 200 ml of chloroform and concentrating the chloroform phase F received.
  • the yield of product (N) is then 8.5 g.
  • the product (F) can also be taken up in ethanol to completely remove chloroform residues and freed of all volatile constituents in vacuo.
  • Further product (A 2 ) can be obtained from the ethanolic phase from the product (P) obtained above by dissolving in absolute ethanol, adding water to a permanent turbidity and then extracting with heptane (approx. 10% of the product P used). .

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EP86900765A 1985-01-18 1986-01-20 Proteinhydrolysate, verfahren zu ihrer herstellung und arzneimittel, die diese hydrolysate enthalten Expired EP0210204B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT86900765T ATE39046T1 (de) 1985-01-18 1986-01-20 Proteinhydrolysate, verfahren zu ihrer herstellung und arzneimittel, die diese hydrolysate enthalten.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE3501560 1985-01-18
DE19853501560 DE3501560A1 (de) 1985-01-18 1985-01-18 Proteinhydrolysate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
DE3518828 1985-05-24
DE19853518828 DE3518828A1 (de) 1985-05-24 1985-05-24 Proteinhydrolysate auf basis von molkenprotein, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel

Publications (2)

Publication Number Publication Date
EP0210204A1 EP0210204A1 (de) 1987-02-04
EP0210204B1 true EP0210204B1 (de) 1988-12-07

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EP86900765A Expired EP0210204B1 (de) 1985-01-18 1986-01-20 Proteinhydrolysate, verfahren zu ihrer herstellung und arzneimittel, die diese hydrolysate enthalten

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US (1) US4918008A (da)
EP (1) EP0210204B1 (da)
JP (1) JPH0732718B2 (da)
AU (1) AU583592B2 (da)
DE (1) DE3661339D1 (da)
DK (1) DK446386A (da)
WO (1) WO1986004217A2 (da)

Families Citing this family (32)

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AU583592B2 (en) * 1985-01-18 1989-05-04 Kailash Kumar Gauri Protein hydrolysates for pharmaceutical use
DK589785A (da) * 1985-12-18 1987-06-19 Samuelsson Ernst Gunnar Peptidpraeparat, fremgangsmaade til fremstilling deraf samt anvendelse af peptidpraeparatet
JP2794305B2 (ja) * 1988-07-20 1998-09-03 明治乳業株式会社 牛乳乳清蛋白質中のβ―ラクトログロブリンの選択的酵素分解方法
DE3829552A1 (de) * 1988-08-31 1990-03-01 Gauri Kailash Kumar Milchbestandteile, verfahren zu ihrer herstellung und mittel, die diese bestandteile enthalten
DE3922453A1 (de) * 1989-07-07 1991-01-17 Gauri Kailash Kumar Pharmakologisch wirksame produkte aus molkeproteinhydrolysaten und verfahren zu deren gewinnung
DK167813B1 (da) * 1989-12-07 1993-12-20 Carlbiotech Ltd As Pentapeptidderivat, farmaceutisk acceptable salte heraf, fremgangsmaade til fremstilling deraf og farmaceutisk praeparat indeholdende et saadant derivat
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JP2818056B2 (ja) * 1990-09-07 1998-10-30 森永乳業株式会社 抗菌性ペプチドおよび抗菌剤
DK53291D0 (da) * 1991-03-25 1991-03-25 Carlbiotech Ltd As Smaa peptider og peptidrelaterede stoffer samt farmaceutiske praeparater indeholdende saadanne forbindelser
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US7618669B2 (en) * 2005-06-01 2009-11-17 Mead Johnson Nutrition Company Low-lactose partially hydrolyzed infant formula
WO2009128713A1 (en) * 2008-04-14 2009-10-22 Newtricious B.V. Egg protein hydrolysates
JP5232725B2 (ja) * 2008-06-04 2013-07-10 森川健康堂株式会社 血圧降下作用を有するローヤルゼリーの製造方法
JP5232726B2 (ja) * 2008-06-04 2013-07-10 森川健康堂株式会社 血圧降下作用を有するローヤルゼリーの製造方法
CN102378581A (zh) * 2009-04-02 2012-03-14 诺维信公司 用于制备基于乳的蛋白质水解产物的方法
JP7561478B2 (ja) * 2017-06-29 2024-10-04 キリンホールディングス株式会社 ステイン付着抑制用口腔組成物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3237837A1 (de) * 1982-10-12 1984-07-19 Kailash Kumar Prof. Dr. 2359 Lentföhrden Gauri Verwendung von atmungsaktiven extrakten als zusatz zu lebens- und genussmitteln
EP0106309A3 (de) * 1982-10-12 1986-12-30 Kailash Kumar Dr. Prof. Gauri Biologisch aktive Extrakte, Verfahren zu deren Herstellung, sie enthaltende pharmazeutische und kosmetische Mittel und ihre Verwendung als Zusätze für Lebens- und Genussmittel
AU583592B2 (en) * 1985-01-18 1989-05-04 Kailash Kumar Gauri Protein hydrolysates for pharmaceutical use

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DK446386D0 (da) 1986-09-17
EP0210204A1 (de) 1987-02-04
DK446386A (da) 1986-09-17
WO1986004217A3 (en) 1986-11-06
AU5359486A (en) 1986-08-13
JPS62501472A (ja) 1987-06-18
US4918008A (en) 1990-04-17
AU583592B2 (en) 1989-05-04
WO1986004217A2 (en) 1986-07-31
DE3661339D1 (en) 1989-01-12
JPH0732718B2 (ja) 1995-04-12

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